Method for synthesis of secondary alcohols

ABSTRACT

A method for synthesis of secondary alcohols is provided for pharmaceutical secondary alcohol by addition of organoboronic acids with aldehydes in presence of the cobalt ion and bidentate ligands as the catalyst. In addition, an enantioselective synthesis method for secondary alcohols is also herein provided in the present invention. The present invention has advantages in using less expensive cobalt ion and commercially available chiral ligands as the catalyst, wide scope of organoboronic acids and aldehydes compatible with this catalytic reaction and achieving excellent yields and/or enantiomeric excess.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for synthesis of secondaryalcohols, particularly to a method for synthesis of secondary alcoholsby addition of organoboronic acids with aldehydes in presence of thecobalt ion and bidentate ligands.

2. Description of the Prior Art

Chiral secondary alcohols are key structural units present in variousbiologically and pharmaceutically active compounds.Transition-metal-catalyzed addition of organometallic reagents withaldehydes is a key method for the synthesis of substituted secondaryalcohols. Among them, organoboronic reagents have gained much attentiondue to the advantages of air and moisture stability, low toxicity, andavailability. Among the transition-metal-catalysts, rhodium, palladium,platinum and nickel complexes efficiently catalyzed the additionreaction of organoboronic acids with aldehydes. Recently, copper- andiron-catalyzed addition reactions of organoboronic acid with aldehydeswere also reported. However, the scope of aldehydes in these additionreactions is rather limited. Only aromatic aldehydes with anelectron-withdrawing substituent worked well. Despite the fact thatvarious metal-catalyzed addition reactions of organoboronic acids withaldehydes are available in the literature, only a few reports onasymmetric reactions were discussed.

Zhou et al. (Org. Lett. 2006, 8, 1479) reported a rhodium-catalyzedenantioselective addition reaction of aromatic boronic acids witharomatic aldehydes. In the reaction, enantiomeric excess (ee) values of62-87% for chiral biaryl methanols were observed.

Recently, Miyaura et al (Angew. Chem. Int. Ed. 2009, 48, 4414) reporteda ruthenium-catalyzed enantioselective addition reaction of aromaticboronic acids with aromatic aldehydes. In the reaction, the expectedchiral biaryl methanols were observed in excellent enantiomeric excess.However, in these reactions specially designed chiral ligands andexpensive ruthenium or rhodium catalysts were used.

To sum up, the development of new, mild and convenient methods using alow-cost catalyst for the synthesis of chiral secondary alcohols remainshighly attractive.

SUMMARY OF THE INVENTION

The present invention is directed to a method for synthesis of secondaryalcohols provided for pharmaceutical secondary alcohol by addition oforganoboronic acids with aldehydes in presence of the cobalt ion andbidentate ligands as the catalyst.

According to one embodiment, a method for synthesis of secondaryalcohols where an organoboronic acid and an aldehyde are reacted in areaction reagent to obtain a secondary alcohol is disclosed, wherein thereaction reagent comprises a cobalt ion and a bidentate ligand.

The present invention is also directed to an enantioselective method forsynthesis of secondary alcohols provided for enantioselective secondaryalcohol by addition of organoboronic acids with aldehydes in presence ofthe cobalt ion and bidentate chiral ligands as the catalyst.

According to another embodiment of the present invention, anenantioselective method for synthesis of secondary alcohols where anorganoboronic acid and an aldehyde in an organic reagent are reacted toobtain an enantioselective secondary alcohol, wherein the organicreagent comprises a cobalt ion and a chiral bidentate ligand.

Other advantages of the present invention will become apparent from thefollowing descriptions taken in conjunction with the accompanyingdrawings wherein certain embodiments of the present invention are setforth by way of illustration and examples.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention is directed to a method for synthesis of secondaryalcohols by addition of organoboronic acids with aldehydes in a reactionreagent including cobalt ion and bidentate ligands conjugated thereto asthe catalyst.

The organoboronic acids of the present invention may include alkyland/or aryl boric acid. Preferably, the organoboronic acids are arylboric acids, particularly phenyl boric acids, which is represented bystructural formula (1):

, wherein R₁ is a member selected from the group consisting of H, halo,cyano, trifluoromethyl, amino, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ cycloalkenyl, C₁-C₂₀heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl, aryl and heteroaryl.

The aldehydes of the present invention are represented by the structuralformula (2):

, wherein R₂ is a member selected from the group consisting of C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀cycloalkenyl, C₁-C₂₀ heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl, aryland heteroaryl.

Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl and heteroaryl mentioned herein include bothsubstituted and unsubstituted moieties, unless specified otherwise.Possible substituents on cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, and heteroaryl include, but are not limitedto, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ cycloalkenyl, C₁-C₂₀ heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl,C₁-C₁₀ alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀alkylamino, C₁-C₂₀ dialkylamino, arylamino, diarylamino, C₁-C₁₀alkylsulfonamino, arylsulfonamino, C₁-C₁₀ alkylimino, arylimino, C₁-C₁₀alkylsulfonimino, arylsulfonimino, hydroxyl, halo, thio, C₁-C₁₀alkylthio, arylthio, C₁-C₁₀ alkylsulfonyl, arylsulfonyl, acylamino,aminoacyl, aminothioacyl, amido, amidino, guanidine, ureido, thioureido,cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl, andcarboxylic ester. On the other hand, possible substituents on alkyl,alkenyl, or alkynyl include all of the above-recited substituents exceptC₁-C₁₀ alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, and heteroaryl can also be fused with eachother.

In one embodiment, diaryl methanols may be obtained as product by usingreactants arylboronic acid and aryl aldehyde.

The cobalt ion used in the present invention may be Co²⁺ or Co³⁺,preferably Co²⁺, and may be provided by Co(acac)₂, CoI₂, CoBr₂ or CoCl₂

The bidentate ligands used in the present invention, for example,include phosphor, nitrogen or oxygen and is used for conjugating withcobalt ion as the catalyst.

For example, bidentate ligands containing phosphor may include DPPE(1,2-bis(diphenylphosphino)ethane), (R)-Prophos((R)-(+)-1,2-bis(diphenylphosphino)propane), (R)-Tol-BINAP((R)-(+)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl), (S)-BINAP((S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl), (S,S)-Chiraphos((2S,3S)-(−)-bis(diphenylphosphino)butane), (R,R)-BDPP(2R,4R)-(+)-2,4-bis(diphenylphosphino)pentane), (S,S)-BDPP(2S,4S)-(+)-2,4-bis(diphenylphosphino)pentane), (R,R)-Ph-BPE((−)-1,2-Bis((2R,5R)-2,5-diphenylphospholano)ethane), (R)-Quinap((R)-(+)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline), (R)-MOP((R)-(+)-2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl), (S,S)-DIPAMP((S,S)-1,2-Bis[(2-methoxyphenyl)(phenylphosphino)]ethane), (R)-Monophos((R)-(−)-(3,5-Dioxa-4-phospha-cyclohepta[2,1-a:3,4-a′]dinaphthalen-4-yl)dimethylamine)or (S,S)-DIOP((4S,5S)-(+)-4,5-Bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane).

For example, bidentate ligands containing nitrogen may include3,5-dimethyl-bispyrazolylmethane, 2,2′-bipyridine or1,1-bis[4,4-dimethyl-1,3-oxazolin-2-yl]ethane.

For example, bidentate ligands containing oxygen may include (S)-BINOL((S)-(−)-1,1′-Bi(2-napthol).

Also in one embodiment, the reaction reagent of the present invention isbasic and provided by K₂CO₃; however, this is a preferred embodiment andis not thus limited.

Referring to Table 1 and the reaction formula listed below, in oneembodiment of the present invention, a secondary alcohol 3 may beobtained from reaction of an arylboronic acid 1 and an aldehyde 2 inpresence of the cobalt ion and bidentate ligand as the catalyst.

TABLE 1 Results of the addition reaction of arylboronic acid withaldehydes_([a]) Yield_([b]) Entries Reactant Product [%] 1 1a: R₁ = H;2a: R₂ = 4-CN—C₆H₄ 3aa 96 2 1a: R₁ = H; 3ab 97 2b: R₂ = 4-NO₂—C₆H₄ 3 1a:R₁ = H; 3ac 93 2c: R₂ = 4-CHO—C₆H4 4 1a: R₁ = H; 3ad 98 2d: R₂ =4-CO₂Me—C₆H₄ 5 1a: R₁ = H; 3ae 89 2e: R₂ = 4-CF₃—C₆H₄ 6 1a: R₁ = H; 2f:R₂ = 4-F—C₆H₄ 3af 92 7 1a: R₁ = H; 2g: R₂ = 3-F—C₆H₄ 3ag 82 8 1a: R₁ =H; 2h: R₂ = 2-F—C₆H₄ 3ah 80 9 1a: R₁ = H; 2i: R₂ = 4-C1—C₆H₄ 3ai 96 101a: R₁ = H; 2j: R₂ = 4-Br—C₆H₄ 3aj 84 11 1a: R₁ = H; 2k: R₂ = Ph 3ak 7312 1a: R₁ = H; 2l: R₂ = 1-napthyl 3al 75 13 1a: R₁ = H; 2m: R₂ =2-napthyl 3am 75 14 1a: R₁ = H; 2n: R₂ = 4-Me—C₆H₄ 3an 67 15 1a: R₁ = H;3ao 57 2o: R₂ = 4-OMe—C₆H₄ 16 1a: R₁ = H; 3ap 76 2p: R₂ = 4-pyridinyl 171a: R₁ = H; 2q: R₂ = 2-furyl 3aq 69 18 1a: R₁ = H; 2r: R₂ = 2-thienyl3ar 78 19 1a: R₁ = H; 2s: R₂ = cyclohexyl 3as 79 20 1b: R₁ = 4-Br; 3bd93 2d: R₂ = 4-CO₂Me—C₆H₄ 21 1c: R₁ = 4-F; 3cd 93 2d: R₂ = 4-CO₂Me—C₆H₄22 1d: R₁ = 4-CHO; 3dd 84 2d: R₂ = 4-CO₂Me—C₆H₄ 23 1e: R₁ = 4-Me; 3ed 922d: R₂ = 4-CO₂Me—C₆H₄ 24 1f: R₁ = 4-OMe; 3fd 97 2d: R₂ = 4-CO₂Me—C₆H₄ 251g: R₁ = 2-OMe; 3gd 96 2d: R₂ = 4-CO₂Me—C₆H₄ 26 1h: R₁ = 4-viny; 3hd 752d: R₂ = 4-CO₂Me—C₆H₄ 27 1i: R₁ = (E)-styryl; 3id 78 2d: R₂ =4-CO₂Me—C₆H₄ _([a])Unless otherwise mentioned, all of the reactions werecarried out by using arylboronic acid 1 (1.20 mmol), aldehydes 2 (1.00mmol), Co(acac)₂ (5 mol %), dppe (5 mol %), and THF/CH₃CN (1:1) at 80°C. for 12 h. _([b])Isolated yields.

Examples 3aa˜3 as

In the above-mentioned reaction condition, various secondary alcoholswere obtained from the addition reaction of phenylboronic acid 1a witharomatic aldehydes, heterocyclic aldehydes, and aliphatic aldehydes.Here, benzaldehydes with electron-withdrawing groups, such as 4-NO₂(2b), 4-CHO (2c), 4-CO₂Me (2d), and 4-CF₃ (2e) provided diarylmethanols3ab-3ae in excellent yields (89-97%; Table 1, entries 2-5).

Halo-substituted benzaldehyde derivatives are also compatible with thepresent catalytic reaction. For example, 4-F (2H), 3-F (2g), 2-F (2h),4-Cl (2i), and 4-Br (2j) also reacted efficiently with 1a to give thecorresponding diarylmethanols 3af-3aj in good to excellent yields (Table1, entries 6-10).

Similarly, benzaldehyde (2k), 1-napthaldehyde (2l) and 2-napthaldehyde(2m) underwent addition reaction with 1a to afford products 3ak-3am ingood yields (Table 1, entries 11-13).

Benzaldehydes containing electron-donating groups, such as 4-Me (2n) and4-OMe (2o) also gave addition products 3an and 3ao albeit in moderateyields (Table 1, entries 14 and 15).

Heterocyclic aldehydes, including 4-formylpyridine (2p), 2-formylfuran(2q), and 2-formylthiophene (2r) also reacted efficiently to giveaddition products 3ap-3ar in 76, 69, and 78% yields, respectively (Table1, entries 16-18).

Aliphatic aldehyde, such as cyclohexanecarbaldehyde (2s), alsoeffectively participated in the addition reaction affording product 3 asin 79% yield (Table 1, entry 19).

Examples 3bd-3id

In addition, various substituted organoboronic acids were reacted withmethyl 4-formyl benzoate (2d). Substituents 4-Bromo (1b), 4-fluoro (1c),4-formyl (1d), 4-methyl (1e), 4-methoxy (1f), 2-methoxy (1g) and4-vinylphenylboronic (1h) acids all reacted effectively with 2d tofurnish substituted diarylmethanols 3bd-3hd in 93, 93, 84, 92, 97, 96,and 75% yield, respectively (Table 1, entries 20-26).

These results clearly indicate that the present addition reaction showsexcellent tolerance towards Br, F, CHO, Me, and OMe functional groups.

The catalytic reaction also worked very well with alkenylboronic acid.Thus, (E)-1-styrylboronic acid (11) reacted with 2d to afford allylicalcohol 31d in 78% yield (Table 1, entry 27).

Example Results with Different Catalysts Used

Treatment of phenylboronic acid (1a) with 4-cyanobenzaldehyde (2a) inpresence of Co(acac)₂ (5 mol %), 1,2-bis(diphenylphosphino)ethane (dppe;5 mol %) in THF/CH₃CN (1/1) at 80° C. for 12 h gave addition product 3aain 96% isolated yield (Table 1, entry 1).

In the present reaction, no extra base was required and only 1.2 mmol ofboronic acid was used. The catalytic reaction also worked equally wellusing CoI₂ or CoCl₂ (5 mol %), dppe (5 mol %) as the catalyst, and THFas solvent to afford 3aa in 96-97% yield, but base (K₂CO₃ (1.50 equiv))was needed to activate the boronic acid.

Enantioselective Secondary Alcohols

Referring to Table 2 and the reaction formula listed below, the presentinvention is also directed to a secondary alcohol 3 obtained fromreaction of an arylboronic acid 1 and an aldehyde 2 in presence of thecobalt ion and bidentate ligand as the catalyst.

TABLE 2 Results of the enantioselective addition reaction of variousphenylboronic acids with substituted aldehydes._([a]) Yield_([b])Entries Reactant Product (ee)[%] 1 1a: R₁ = H; (S)-3aa 97 (92) 2a: R₂ =4-CN—C₆H₄ 2 1a: R₁ = H; (S)-3ab 95 (93) 2b: R₂ = 4-NO2—C₆H₄ 3 1a: R₁ =H; (S)-3ad 98 (94) 2d: R₂ = 4-CO₂Me—C₆H₄ 4 1a: R₁ = H; (R)-3ad 95_([c])(93) 2d: R₂ = 4-CO₂Me—C₆H₄ 5 1a: R₁ = H; (S)-3ae 97 (92) 2e: R₂ =4-CF3—C₆H₄ 6 1a: R₁ = H; 2f: R₂ = 4-F—C₆H₄ (S)-3af 95 (99) 7 1a: R₁ = H;2i: R₂ = 4-Cl—C₆H₄ (S)-3ai 97 (93) 8 1a: R₁ = H; 2j: R₂ = 4-Br—C₆H₄(S)-3aj 97 (96) 9 1a: R₁ = H; 2l: R₂ = 1-napthyl (S)-3al 77 (89) 10 1a:R₁ = H; 2m: R₂ = 2-napthyl (S)-3am 89 (92) 11 1a: R₁ = H; (S)-3an 90(93) 2n: R₂ = 4-Me—C₆H₄ 12 1a: R₁ = H; (S)-3ao 85 (92) 2o: R₂ =4-OMe—C₆H₄ 13 1a: R₁ = H; 2r: R₂ = 2-thienyl (S)-3ar 82 (86) 14 1a: R₁ =H; (R)-3as 84 (97) 2s: R₂ = cyclohexyl 15 1b: R₁ = 4-Br; (+)-3bd 99 (90)2d: R₂ = 4-CO₂Me—C₆H₄ 16 1b: R₁ = 4-Br; 2k: R₂ = Ph (R)-3bk 84 (94)(R)-3aj 17 1e: R₁ = 4-Me; 2k: R₂ = Ph (R)-3ek 91 (95) (R)-3an 18 1f: R₁= 4-OMe; 2k: R = Ph (R)-3fk 93 (94) (R)-3ao 19 1e: R₁ = 4-Me; (+)-3ed 95(91) 2d: R = 4-CO₂Me—C₆H₄ 20 1f: R₁ = 4-OMe; (+)-3fd 97 (94) 2d: R =4-CO₂Me—C₆H₄ 21 1g: R₁ = 2-OMe; (+)-3gd 92 (90) 2d: R = 4-CO₂Me—C₆H₄_([a])Unless otherwise mentioned, all of the reactions were carried outby using arylboronic acid 1 (1.50 mmol), aldehydes 2 (1.00 mmol), CoI₂(5 mol %), (R,R)-BDPP (5 mol %), K₂CO₃ (1.5 equiv) and THF (2.0 ml) at80° C. for 12 h. _([b])Isolated yields. _([c])(S,S)-BDPP was used.

Examples for Selecting Ligands and Cobalt Ions

Various bidentate chiral ligands, including (R)-Prophos, (R)-Tol-BINAP,(S)-BINAP, (S,S)-Chiraphos, (S)-BINOL, (R,R)-Ph-BPE, (R)-Quinap,(R)-MOP, (S,S)-DIPAMP, (R)-Monophos, (R,R)-BDPP, (S,S)-BDPP and(S,S)-DIOP, were adopted and examined in the present invention.

Phenylboronic acid (1a) and 2d were used as the model substrates in thisstudy, where cobalt catalyst CoI₂ (5 mol %), a bidentate chiral ligand(5 mol %), and K₂CO₃ (1.5 equiv) in THF were used. Among the testedligands, (R,R)-BDPP is most effective, affording (S)-diarylmethanol 3adin 98% yield with an ee value of 94% (Table 2, entry 3). Other ligandsprovided 3ad in 44-86% yields with an ee value of 10-67%.

Under the reaction conditions, (S,S)-BDPP provided the other enantiomer(R)-diarylmethanol 3ad in 95% yield with an ee of 93% (Table 2, entry4).

Another cobalt catalyst, C (acac)₂/(R,R)-BDPP, in THF without base isalso effective, giving chiral (S)-3ad in 95% yield and 93% ee.

Examples 3aa-3 as

Referring to Table 2 and the reaction formula, in presence of CoI₂ (5mol %)/(R,R)-BDPP (5 mol %) and K₂CO₃ (1.5 equiv) in THF, the reactionof various substituted aldehydes with phenylboronic acid (1a) were thenexamined.

Electron-withdrawing groups, 4-CN (2a), 4-NO₂ (2b), 4-CO₂Me (2d), and4-CF₃ (2e) substituted benzaldehydes afforded chiral (S)-diarylmethanols3aa, 3ab, 3ad, and 3ae in excellent 97, 95, 98, and 97% yield with 92,93, 94 and 92% ee, respectively (Table 2, entries 1-3, 5).

Also, if CoI₂/(S,S)-BDPP was employed as the catalyst, the reaction of1a with 2d afforded the corresponding (R)-3ad in 93% ee (Table 2, entry4).

Similarly, by using CoI₂/(R,R)-BDPP as the catalyst, 4-F (2f), 4-Cl (2i)and 4-Br (2j) substituted benzaldehydes may effectively react withphenylboronic acid 1a providing (S)-diarylmethanols 3af, 3ai and 3aj inexcellent 95-97% yield with 99, 93, and 96% ee, respectively (Table 2,entries 6-8).

Likewise, 1-naphth (21) and 2-naphthaldehyde (2m), 4-methyl (2n),4-methoxybenzaldehyde (2o), and 2-formylthiophene (2r) gave(S)-diarylmethanols 3al, 3am, 3an, 3ao, and 3ar, respectively, in 77-90%yield with 86-93% ee (Table 2, entries 9-13).

In a similar manner, cyclohexanecarbaldehyde (2s) yielded (R)-3 as in84% yield with 97% ee (Table 2, entry 14).

Examples 3bd, 3ed, 3fd and 3gd

In addition, other substituted phenylboronic acids, including 4-bromo(1b), 4-methyl (1e), 4-methoxy (1f), and 2-methoxy (1g) phenylboronicacids, also reacted smoothly with 4-CO₂Me substituted benzaldehyde 2d togive diarylmethanols 3bd, 3ed, 3fd, and 3gd in excellent yields (92-99%)and ee values (90-94%), respectively (Table 2, entries 15, 19-21).

It is noteworthy that (R)-3bk is the enantiomer of (S)-3aj (Table 2,entry 8) prepared from phenylboronic acid (1a) and 4-bromobenzaldehyde(2j) using the same chiral CoI₂/(R,R)-BDPP catalyst.

In a similar manner, product (R)-3ek (Table 2, entry 17) is enantiomerof (S)-3an (Table 2, entry 11) and (R)-3fk (Table 2, entry 18) is theenantiomer of (S)-3ao (Table 2, entry 12).

Thus, the present catalytic asymmetric addition reaction provides aversatile method to prepare the two enantiomers by using the same chiralcatalyst. Moreover, in the present asymmetric reaction, products (S)-3aiand (R)-3ek are known to be the key intermediates for biologicallyactive compounds (S)-cetirizine and (R)-neobenodine, respectively.

To sum up, the method for synthesis of secondary alcohols of the presentinvention may obtain pharmaceutical secondary alcohol with excellentyields and/or enantiomeric excess by addition of organoboronic acidswith aldehydes in presence of the cobalt ion and bidentate ligands asthe catalyst. The present invention may also have advantages in usingless expensive cobalt ion and commercially available chiral ligands(such as (R,R)-BDPP) as the catalyst and wide scope of organoboronicacids and aldehydes compatible with this catalytic reaction.

While the invention can be subject to various modifications andalternative forms, a specific example thereof has been shown in thedrawings and is herein described in detail. It should be understood,however, that the invention is not to be limited to the particular formdisclosed, but on the contrary, the invention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the appended claims.

1. A method for synthesis of secondary alcohols, comprising: reacting anorganoboronic acid and an aldehyde in a reaction reagent to obtain asecondary alcohol, wherein the reaction reagent comprises a cobalt ionand a bidentate ligand.
 2. The method as claimed in claim 1, wherein theorganoboronic acid is an arylboronic acid.
 3. The method as claimed inclaim 1, wherein the organoboronic acid is a phenylboronic acidrepresented by a structure formula (1):

, wherein R₁ is a member selected from the group consisting of H, halo,cyano, trifluoromethyl, amino, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ cycloalkenyl, C₁-C₂₀heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl, aryl and heteroaryl.
 4. Themethod as claimed in claim 1, wherein the aldehyde is represented by astructure formula (2):

, wherein R₂ is a member selected from the group consisting of C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀cycloalkenyl, C₁-C₂₀ heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl, aryland heteroaryl.
 5. The method as claimed in claim 1, wherein thebidentate ligand contains phosphor.
 6. The method as claimed in claim 5,wherein the bidentate ligand comprises DPPE, (R)-Prophos, (R)-Tol-BINAP,(S)-BINAP, (S,S)-Chiraphos, (R,R)-Ph-BPE, (R)-Quinap, (R)-MOP,(S,S)-DIPAMP, (R)-Monophos, (R,R)-BDPP or (S,S)-DIOP.
 7. The method asclaimed in claim 1, wherein the cobalt ion is Co²⁺.
 8. The method asclaimed in claim 1, wherein the cobalt ion is provided by Co(acac)₂,CoI₂, CoBr₂ or CoCl₂.
 9. The method as claimed in claim 1, wherein thereaction reagent is basic.
 10. The method as claimed in claim 9, whereinthe basic reaction reagent is provided by K₂CO₃.
 11. An enantioselectivemethod for synthesis of secondary alcohols, comprising: reacting anorganoboronic acid and an aldehyde in an organic reagent to obtain anenantioselective secondary alcohol, wherein the organic reagentcomprises a cobalt ion and a chiral bidentate ligand.
 12. The method asclaimed in claim 11, wherein the organoboronic acid is an arylboronicacid.
 13. The method as claimed in claim 11, wherein the organoboronicacid is a phenylboronic acid represented by a structure formula (1):

, wherein R₁ is a member selected from the group consisting of H, halo,cyano, trifluoromethyl, amino, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ cycloalkenyl, C₁-C₂₀heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl, aryl and heteroaryl. 14.The method as claimed in claim 11, wherein the aldehyde is representedby a structure formula (2):

, wherein R₂ is a member selected from the group consisting of C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀cycloalkenyl, C₁-C₂₀ heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl, aryland heteroaryl.
 15. The method as claimed in claim 11, wherein thebidentate ligand contains phosphor.
 16. The method as claimed in claim15, wherein the bidentate ligand comprises (R)-Prophos, (R)-Tol-BINAP,(S)-BINAP, (S,S)-Chiraphos, (R,R)-Ph-BPE, (R)-Quinap, (R)-MOP,(S,S)-DIPAMP, (R)-Monophos, (R,R)-BDPP or (S,S)-DIOP.
 17. The method asclaimed in claim 11, wherein the cobalt ion is Co²⁺.
 18. The method asclaimed in claim 11, wherein the cobalt ion is provided by Co(acac)₂,CoI₂, CoBr₂ or CoCl₂.
 19. The method as claimed in claim 11, wherein theorganic reagent is basic.
 20. The method as claimed in claim 19, whereinthe basic organic reagent is provided by K₂CO₃.